Dopamine D1/D5 receptor modulates state-dependent switching of soma-dendritic Ca2+ potentials via differential protein kinase A and C activation in rat prefrontal cortical neurons

To determine the nature of dopamine modulation of dendritic Ca2+ signaling in layers V - VI prefrontal cortex (PFC) neurons, whole-cell Ca2+ potentials were evoked after blockade of Na+ and K+ channels. Soma-dendritic Ca2+ spikes evoked by suprathreshold depolarizing pulses, which could be terminated by superimposed brief intrasomatic hyperpolarizing pulses, are blocked by the L-type Ca2+ channel antagonist nimodipine (1 muM). The D1/D5 receptor agonist dihydrexidine (DHX) (0.01 - 10 muM; 5 min) or R-(+) SKF81291 (10 muM) induced a prolonged (>30 min) dose-dependent peak suppression of these Ca2+ spikes. This effect was dependent on [Ca2+](i)- and protein kinase C(PKC)-dependent mechanisms because [Ca2+](i) chelation by BAPTA or inhibition of PKC by bisindolymaleimide (BiM1), but not inhibition of [Ca2+](i) release with heparin or Xestospongin C, prevented the D1-mediated suppression of Ca2+ spikes. Depolarizing pulses subthreshold to activating a Ca2+ spike evoked a nimodipine-sensitive Ca2+ hump potential. D1/D5 stimulation induced an N-[2-((o-bromocinamyl) amino) ethyl]-5-isoquinolinesulfonamide (H-89)- or internal PKA inhibitory peptide([5-24])-sensitive (PKA-dependent) transient (similar to7 min) potentiation of the hump potential to full Ca2+ spike firing. Furthermore, application of DHX in the presence of the PKC inhibitor BiM1 or internal PKC inhibitory peptide[ 19 - 36] resulted in persistent firing of full Ca2+ spike bursts, suggesting that a D1/D5 - PKA mechanism switches subthreshold Ca2+ hump potential to fire full Ca2+ spikes, which are eventually turned off by a D1/D5-Ca2+-dependent PKC mechanism. This depolarizing state-dependent, D1/D5-activated, bi-directional switching of soma-dendritic L-type Ca2+ channels via PKA-dependent potentiation and PKC-dependent suppression may provide spatiotemporal regulation of synaptic integration and plasticity in PFC.